Vaginal rings are known. Background art in this respect includes the following patent documents.
U.S. Pat. Nos. 3,995,633 and 3,995,634, describe separate, preferably spherical or cylindrical, reservoirs containing different active substances, which are assembled in specially constructed holders.
U.S. Pat. No. 4,237,885 describes a tube or coil of polymeric material which is divided into portions by means of a plurality of “spacers” provided in the tube, after which each of the separate tube portions is filled with a different active substance in a silicone fluid and the two ends of the tube are subsequently connected to one another. In this release system, however, transport (diffusion) of active material from one reservoir to the other takes place through the wall of the tube, especially upon prolonged storage, so that the pre-set fixed release ratio between the active substances in question will change over time.
European patent publication 0,050,867 discloses a two-layered vaginal ring which comprises a pharmacologically acceptable supporting ring covered by two layers preferably of silicone elastomers whereby the inner layer is a silicone elastomer loaded with an active substance.
U.S. Pat. No. 4,292,965 describes a ring shaped vaginal delivery system of three layers made of silicone elastomers.
U.S. Pat. No. 4,596,576 describes a two-compartment vaginal ring wherein each compartment contains a different active substance. To achieve a suitable ring with a constant release ratio between the various active substances, the end portions of the compartments are joined by glass stoppers.
Patent Publication WO 97/02015 describes a two-compartment device, a first compartment consisting of a core, a medicated middle layer and a non medicated outer layer, and a second compartment consisting of a medicated core and a non medicated outer layer.
EP 876 815 discloses a vaginal ring (Nuvaring®) which is designed for the simultaneous release of a progestogenic steroid compound and an estrogenic steroid compound in a fixed physiological ratio over a prolonged period of time. The drug delivery system comprises one compartment comprising a thermoplastic polymer core containing the mixture of the progestogenic and estrogenic compounds and a thermoplastic polymer skin, the progestogenic compound being initially dissolved in the polymer core material in a relatively low degree of supersaturation.
Patent Publication WO2004/103336 describes a drug delivery system comprising at least one compartment consisting of a drug-loaded thermoplastic polymer core, a drug-loaded thermoplastic polymer intermediate layer and a non-medicated thermoplastic polymer skin covering the intermediate layer. The intermediate layer is loaded with crystals of a progestogenic compound and with estrogenic compound in a dissolved form. The core is loaded with the estrogenic compound in a dissolved form.
Patent publication WO2005/089723 discloses a ring with one or more compartments in which one compartment comprises a core in which a progestogenic compound is dissolved up to a concentration below the saturation level at 25° C. The core also comprises an estrogenic compound. The compartment furthermore comprises a skin that is permeable for both the progestogenic and estrogenic compound.
From the above disclosures, it is clear that e.g. the material, the layers and the compartments are all aspects which play a role in the development of a ring device.
All choices are usually made with a view to obtain a constant release pattern, which is complicated when two or more active substances are involved. The latter is of particular importance in the field of contraception, as for this purpose often a combination of a progestogen and an estrogen is used, the release pattern of which must result in a contraceptive effect. Also in hormone replacement therapy, it may be desired to have rings, which deliver combinations of drugs.
Among the above disclosures, EP 876 815, WO2005/089723 and WO2004/103336 clearly set a standard; they involve one-compartment ring designs, they obviate the need for silastic polymer by using ethylene vinyl acetate (EVA) combinations, and they release two or more active substances in a substantially constant ratio to one another over a prolonged period of time.
As any product of technology at all times however, also the latter can still be improved upon. The drug delivery devices described in EP 876 815, WO2005/089723 and WO 2004/103336 require that all active compounds are present in the dissolved state (EP 876 815 and WO2005/089723) or that all compounds except for one (WO 2004/103336) are present in the dissolved state. This prerequisite severely limits the amount of drug that can be loaded into the polymeric matrix. An increase of the drugs concentration above a certain critical threshold value (J. van Laarhoven et al, Journal of Controlled Release, 82, 2002, p 309-317) will inevitably result in crystallization of the drug in the polymeric matrix. Consequently, the drug delivery systems disclosed in both EP 876 815, WO2005/089723 and WO 2004/103336 are not suitable when using two pharmaceutically active compounds which are both present in a solid state. This may happen when the active compounds have a relatively poor solubility in the polymers used, such as EVA polymers, and/or require a relatively high drug load in the polymeric matrix in order to obtain the required release pattern. When both drug substances are present in the crystalline form, the dissolved concentration of both compounds is per definition the saturation concentration of each compound. Consequently, it is not possible to adjust the release rate of one of such pharmaceutically active compounds independently from the other, by varying the concentration of the active compounds as their concentration will remain equal to their saturation concentration. Variation of the skin thickness will also not contribute to the adjustment of the release rate of one of such pharmaceutically active compounds independently from the other because an increase or a decrease of the skin thickness will influence the release of both compounds in the same direction.
It is therefore the object of the present invention to provide a drug delivery system in which the release rate of the two compounds that are partly present in the solid state and partly in the dissolved state can be regulated independently from one another.